PROJECT SUMMARY/ABSTRACT (PROJECT 3) Increasing numbers of human ailments, including inflammatory bowel disease (IBD), metabolic syndrome, and diabetes, have been linked to disturbances in resident microbial communities. In these diseases, no single infectious organism is implicated, but instead abnormal, also called dysbiotic microbial communities, often characterized by an overabundance of pro-inflammatory taxa and an underrepresentation of anti- inflammatory taxa, are implicated in causing disease symptoms. Mounting evidence suggests that pro- inflammatory microbiota can be self-perpetuating because the inflamed host environment selects for microbes that promote and thrive on conditions that perpetuate inflammation. We hypothesize that transmission of pro- inflammatory microbiota members increases the likelihood of developing disease, and that this transmission is enhanced by the absence of anti-inflammatory taxa that would normally curtail a chronically inflamed host environment. We hypothesize that transmissible anti-inflammatory strains would be useful not only for alleviating inflammation in individual hosts, but for spreading resistance to pro-inflammatory strains, thereby creating herd immunity to disease-causing strains similar to vaccination. We propose to engineer microbiota members that function as ?smart probiotics? to sense and alleviate host inflammation in a modulated and local fashion. We will determine how to tune the therapeutic and transmission properties of these smart probiotics to optimize their capacity to treat inflammation in individual hosts and to disseminate sufficiently between hosts to generate protection against the spread of pro-inflammatory strains on a population scale. These experiments will establish the design principles for engineering transmissible health.